Hyperglycemia per se is an important factor in the serious complications which associate with diabetes mellitus. Failure of insulin to suppress hepatic glucose production in the fasting state is a fundamental concomitant of fasting hyperglycemia, and is a contributor to postprandial glucose intolerance. Understanding the regulation by insulin of liver glucose output is requisite to understanding Type 1 and Type 2 diabetes. Such understanding could lead to improvements in prediction of the onset of the disease, and improvements in therapy. The physiologic mechanisms of control of hepatic glucose release by insulin are completely understood. Insulin can act directly at the liver, and/or indirectly via other tissues to regulate the two sources of glucose output, glycogenolysis and gluconeogenesis. Recent data from this and other laboratories indicates that the importance of extrahepatic mechanisms been underestimated. This has been due to systemic methodologic inaccuracies in measuring liver glucose release, as well as experimental protocols which may not have clearly addressed this question. It is the primary goal of the studies outlined in this application to examine the relative importance and underlying mechanisms of hepatic versus extrahepatic regulation of hepatic glucose production in normal animals, and how these mechanisms are altered in conditions of insulin resistance and diabetes. We are exploiting a novel protocol in which only portal or peripheral insulins are changed, but the alternative concentration is approximately matched. We will test the hypothesis that suppression of HGO by insulin is dominated by a peripheral rather than a direct hepatic effect of the hormone. This will entail examination of the relative importance of insulin inhibition of gluconeogenesis versus glycogenolysis in the indirect effects of the hormone. We will attempt to elucidate the "negative feedback signal" which mediates insulin's extrahepatic effect to suppress liver glucose output. Additionally, we propose to examine alterations in the relative direct and indirect effects of insulin after fasting with changes in diet as well as in pathophysiologic conditions including insulin resistance and experimental diabetes. These studies should clarify the mechanism of insulin resistance at the level of glucose output in experimental diabetes, and could lead to improved therapy to regulate glycemia in this disease.